Radiotherapeutic management of cervical lymph node metastases from an unknown primary site - experiences from a large cohort treated with modern radiation techniques

Abstract

Purpose: To analyze management and outcomes following (chemo)radiation therapy in patients with cervical lymph node metastases from an unknown primary site (CCUP) in a large single-center cohort.

Methods: Between 2008 and 2019, 58 patients with CCUP were treated with (chemo)radiation therapy at the University of Freiburg Medical Center and were included in this analysis. Overall survival (OS), locoregional progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The use of diagnostic procedures and their impact on oncological outcomes was analyzed by Cox regression, and treatment-related toxicities were quantified.

Results: Median follow-up was 29.9 months (range 4.6-121.9). Twenty-one patients (36.2%) received definitive RT, 35 (60.3%) underwent adjuvant RT, and 2 (3.4%) were treated for oligometastatic disease. Concurrent chemotherapy was prescribed in 40 patients (69.0%). 89.6% of patients completed the prescribed RT, and 65.0% completed the prescribed simultaneous chemotherapy. Locoregional recurrence was observed in 7 patients (12.1%) and distant metastases in 13 cases (22.4%). OS was 81,1, 64.9% and 56,6% after 1, 3 and 5 years, respectively. Univariate analysis of age, gender, extracapsular spread, tumor grading, neck dissection, diagnostic utilization of ¹⁸F-fluorodeoxyglucose positron-emission tomography and concomitant chemotherapy showed no effect on OS (p > 0.05 for all), while smoking was significantly associated with decreased survival (p < 0.05). There was a trend towards impaired OS for patients with advanced nodal status (pN3) (p = 0.07). Three patients (5.2%) experienced grade 3 radiation dermatitis, and 12 (22.4%) developed grade 3 and 1 (1.7%) grade 4 mucositis.

Conclusions: RT of the panpharynx and cervical lymph nodes with concurrent chemotherapy in case of risk factors demonstrated good locoregional control, but the metachronous occurrence of distant metastases limited survival and must be further addressed.

Keywords: CUP; Carcinoma of unknown primary; Chemotherapy; Head-and-neck cancer; Lymph node; Radiotherapy.

Fig. 1

Adjuvant chemoradiotherapy for a CCUP in a 70-year-old male patient. (A) Pretherapeutic sonography, CT and MRI imaging (a) in December 2017 showed a pathological lymph node in level IIa on the left side and a suspicious lymph node in level II on the right side. A panendoscopy with multiple biopsies of different mucosal regions revealed no primary tumor. As the patient had a tonsillectomy as child, no additional tonsillectomy was performed. The recommended FDG-PET-CT was not conducted, as the costs were not covered by the patient’s health insurance. After bilateral ND in January 2018, pathological assessments showed one necrotic lymph node (1.4 cm diameter) with poorly differentiated (G3), HPV-positive squamous cell carcinoma cells in left-sided level IIa, giving a cTx pN1 cM0 CCUP according to the 7th Edition of the UICC TNM classification. Based on the recommendations of the multidisciplinary tumor board, an adjuvant cisplatin-based chemoradiotherapy with intensity-modulated radiotherapy was performed between March and April 2018. The elective lymphatic drainage and mucosa received 50 Gy in 25 fractions, while the high-risk PTV was treated with a sequential boost of 10 Gy delivered in 5 fractions. (b, c and d) Dose distribution of a volumetric modulated arc therapy plan in an axial (b), sagittal (c) and coronary (d) scan image. The last follow-up in March 2019 showed no signs of recurrence

Fig. 2

Kaplan-Meier curves showing OS (a), PFS (locoregional) (b) and DMFS (c) of CCUP patients treated by radiotherapy (n = 58). The red area shows the 95% confidence intervals for the survival rates

Fig. 3

Kaplan-Meier curves demonstrating OS according to smoking status (a), pathological nodal status (b), age (c) and FDG-PET-CT imaging (d). Log-rank tests were performed to compare the groups